Human immunodeficiency virus (HIV) infection in the central nervous system is characterized by dementia and deficits in motor functions. Cerebral metabolic effects of gp120 (a HIV viral envelope glycoprotein), which binds to brain membranes and T-lymphocytes, were studied in rats. Intracerebroventricular injection of gp120 reduced the regional cerebral metabolic rate for glucose in the lateral habenula and the suprachiasmatic nucleus, and produced an overall decrease in glucose metabolism. As reduced glucose metabolism is observed using positron emission tomography in humans presenting with HIV-associated dementia, the findings suggest that gp120 can alter neuronal function and contribute to HIV-related dementia. As intravenous drug abusers show an abnormally high incidence of HIV infection, animal studies were performed to determine if chronic exposure to abused substances alters immune function. Mice receiving chronic opioid treatment had fewer circulating T-lymphocytes (helpers and suppressor/cytotoxic) than concurrent controls. The effect was dose-dependent, was not blocked by treatment with the opioid antagonist naltrexone, and could be observed within 24 h of initiation of treatment. Oxymorphone caused a similar effect. Morphine treatment did not affect mitogen-stimulated lymphocyte proliferation. This work suggests that morphine compromises immunocompetency and that the use of opioids by intravenous drug abusers may increase the incidence of infection subsequent to exposure to bacterial and viral agents.